Delivery of drugs to patients, with the goal of having the drugs enter the bloodstream, or of acting locally without entry into the blood, can be performed using a variety of methods. For example, certain drugs are delivered to patients by oral ingestion and enter into the bloodstream though the digestive tract. Oral delivery of drugs, however, has disadvantages. One disadvantage is that there can be extensive metabolism and breakdown of an orally-administered drug in the digestive tract, before it reaches the bloodstream, so that only a fraction of the drug ingested actually reaches the bloodstream. Protein and peptide therapeutics, for example, have very poor stability in the digestive tract and are difficult to administer orally. Another disadvantage of drug delivery by the oral route is that the time required for an ingested drug to enter the bloodstream may be quite long. Finally, ingestion of drugs can cause the patient to experience an upset stomach.
Another method for drug delivery is the parenteral route, also called injection. However, injection is an invasive method of delivery in that the skin of the patient must be punctured. Not only is skin puncture painful to the patient, puncture increases the possibility for infection of the patient by various pathogenic microorganisms. In addition, patients may be reluctant or unable to inject themselves for the purpose of administering a drug.
New routes of drug delivery have emerged which alleviate some of the problems inherent in more traditional drug delivery methods discussed above. Pulmonary or respiratory drug delivery is one new method of drug delivery. In respiratory drug delivery, the drug is inhaled into the lungs of the patient. Inhalation of the drug is accomplished through the use of aerosols or inhalers, for example. Once in the lungs, the drug enters the bloodstream by passage through the lung alveoli. Alternatively, the drug can remain in the respiratory tract and act locally, as in the case of asthma, for example.
Respiratory delivery of drugs has a number of advantages. First, drug delivery by inhalation is not invasive and is very convenient for the patient. Respiratory delivery is suitable for drugs that cannot be delivered orally because many drugs are relatively stable in the lungs. Another advantage of respiratory drug delivery is the tremendous surface area available in the alveoli of the lung, close to 70 square meters per lung, through which the inhaled drug can enter the bloodstream. The result of this large surface area is rapid entry of the drugs into the bloodstream. Drug delivery via the pulmonary route also avoids first pass hepatic and renal effects, common to other modes of drug delivery, which remove the drugs from the body.
Also of importance is that some very important human diseases afflict the respiratory tract, including the lung. Asthma is one such disease. Cystic fibrosis is another such disease. Respiratory delivery of drugs is especially important for these diseases because delivery directly to the respiratory tract allows the drugs to act locally, where the drug effect is needed to alleviate symptoms of the disease. In order to treat such diseases, it is not necessary for the inhaled drugs to enter the systemic circulation.
Although rapid entry of drugs into the bloodstream in respiratory delivery is advantageous, usually little drug is left in the lungs 2–3 hours after inhalation. This can be problematic, especially in cases in which it would be advantageous to slowly release drug into the bloodstream over a period of time, or in cases where it is desired to have the drug remain in the lungs to act locally. To presently achieve slow release, repeated low-level dosing of the drug is required. Heretofore, there has been a lack of success in obtaining inhaled drug formulations that would increase drug residence time in the lung and control the release rate of the drug into the bloodstream. Different formulations of inhaled drugs have been tried in an attempt to solve this problem. However, these formulations, both dry powder and liquid formulations, have not resulted in reproducible increased duration of drug in the lungs, nor extended release of inhaled drugs into the bloodstream, without creating new problems, such as the presence of synthetic polymer or other dry powder excipients in the lung.
The lack of delivery systems resulting in controlled release has been disadvantageous for agents other than drugs. For example, X-ray based imaging techniques (including Computed Tomography or CT) and Magnetic Resonance Imaging (MRI) techniques utilize contrast-enhancing agents. Contrast-enhancing agents are delivered to tissues of the body, are localized therein, and have the effect of differentiating the tissue from surrounding tissues that have not localized the agents when the imaging techniques are used. There are no good delivery systems that result in controlled release of contrast-enhancing agents for imaging.
Therefore, because of the difficulties in achieving long term or controlled release of drugs and contrast-enhancing agents using respiratory delivery, there is a need for inhaled delivery systems that provide controlled release of drugs or contrast-enhancing agents from a reservoir that has been inhaled into the lungs. There is a need for the controlled release of drugs and contrast-enhancing agents from the lungs to be of two types. First, systems that provide a relatively slow and constant rate release from a reservoir of drug inhaled into the lungs are needed. Second, systems that provide variable and controllable rates of drug release from a reservoir of drug in the lungs are needed. In systems that provide for controllable release of drug from the lungs, it would further be desirable if the rate of drug release from the lungs could be controlled even after the drug has been inhaled into the lungs.